US11708320B2 - Environmentally-friendly hydroazidation of olefins - Google Patents

Environmentally-friendly hydroazidation of olefins Download PDF

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US11708320B2
US11708320B2 US17/253,966 US201917253966A US11708320B2 US 11708320 B2 US11708320 B2 US 11708320B2 US 201917253966 A US201917253966 A US 201917253966A US 11708320 B2 US11708320 B2 US 11708320B2
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Hao Xu
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/04—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/12—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/14—Compounds containing azido groups with azido groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D347/00—Heterocyclic compounds containing rings having halogen atoms as ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1896—Compounds having one or more Si-O-acyl linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

Definitions

  • the present invention provides processes for the synthesis of organic azides, intermediates for the production thereof, and compositions related thereto.
  • Nitrogen atoms are common components of small-molecule pharmaceuticals and other biomaterials. While processes for the introduction of nitrogen into molecules by functional group transformations have been employed for decades, those that proceed by the direct functionalization of inexpensive hydrocarbon starting materials are less common. Processes for hydrocarbon nitrogen functionalization that avoid the use of toxic transition metals are even rarer. Heavy metal contamination must be removed or avoided altogether in the synthesis of compounds that are intended for use in biological systems. Further, many well-established processes for the introduction of nitrogen in molecules are not environmentally friendly due to their use of stoichiometric levels of reagents.
  • the present invention provides processes for the synthesis of organic azides or azide-functionalized oligomers or polymers by the reaction of an olefin, a silyl azide, and a hydrogen bond donor in the presence of an organic promoter, which is accomplished in an environmentally-friendly and atom-economical manner that does not require the use of metal catalysis.
  • the organic azides provided hereby can be used to create a wide range of nitrogen-containing organic molecules, including those of pharmaceutical and biological interest.
  • the process can also be used to make nitrogen-containing industrial organic compounds.
  • the present processes allow for the synthesis of organic azides from cheap olefin feedstocks instead of more expensive pre-functionalized materials that often require multiple transformations and purifications to obtain the desired product.
  • the present process is significantly more atom economical than previous azide synthetic processes that produced stoichiometric levels of byproducts.
  • the processes described herein also allow for the direct synthesis of hydroazidation products without the use of heavy metals, instead using an organic promoter to mediate the transformation.
  • the prior art metal-mediated or catalyzed transformations often require significant additional purification steps to remove metal contaminants from the final products. This is particularly necessary in pharmaceutical and biological applications where metal contamination can often have detrimental toxicity.
  • the lack of heavy metals avoids the risk of accidental formation of explosive metal azide byproducts.
  • the present processes are also safer for operators because they avoid the use of stoichiometric quantities of the highly volatile, toxic, and explosive reagent hydrazoic acid, and instead use silyl azide reagents that are commercially available and easier to handle.
  • the presently disclosed processes are redox neutral, avoiding the use of stoichiometric oxidants, stoichiometric reductants, or the use of energy-intensive electrochemical processes to facilitate the transformation, an improvement over many azidation processes that have been previously reported.
  • the currently disclosed process goes through a free radical-based mechanism to produce the organic azides from simple olefins.
  • alkyl azides are typically prepared by nucleophilic displacement of a leaving group, such a halogen or sulfonate, with sodium azide. Hydroazidation reactions involving addition across a double bond have been more rarely reported. Markovnikov addition of hydrazoic acid (HN 3 ) has been reported across a limited subset of strained and reactive olefins, most likely preceding through the intermediacy of stabilized tertiary and benzylic carbocations (see Hassner, A. et al. Journal of Organic Chemistry 1984, 49, 4237; and Breton, G. W. et al. Journal of Organic Chemistry 1992, 57, 6646).
  • HN 3 Markovnikov addition of hydrazoic acid
  • Hao Xu and coworkers have reported on an iron-catalyzed diazidation reaction of olefins that uses a stoichiometric amount of either a benziodoxole or organic peroxide oxidant (see Yuan, Y.-A. of al. Angewandte Chemie International Edition 2016, 55, 534; Zhu, H.-T. et al. Organic Process Research Development 2017, 21, 2068; and Shen, S.-J. et al. ACS Catalysis 2018, 8, 4473). While this reaction scheme advances the art, it still includes the use of metal catalysis.
  • the azide is typically added in an anti-Markovnikov orientation across the double bond.
  • this process provides a means to obtain anti-Markovnikov nitrogen-bearing addition products in an environmentally friendly fashion.
  • a process for the synthesis of an organic azide comprising combining an olefin, a silyl azide, a hydrogen bond donor, and an organic promoter such that an organic azide is formed.
  • a process for the synthesis of an organic azide of Formula III comprising mixing an olefin of Formula I, a silylazide of Formula II, a hydrogen bond donor, and an organic promoter such than an organic azide of III is formed.
  • a process for the synthesis of an organic azide is provided as illustrated in Scheme 1:
  • R 1 and R 2 are independently selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, and heterocycloalkyl, wherein each of R 1 and R 2 that is not hydrogen may be optionally substituted with one or more substituents that do not adversely affect the desired reaction, for example a substituent selected from oxo, halo, cyano, azido, nitro, R 7 , —NOR 7 , —N(R 7 ), —(C ⁇ O)R 7 , —(C ⁇ O)OR 7 , —(C ⁇ O)N(R 7 )(R 7 ), —O(C ⁇ O)R 7 , —N(R 7 )(C ⁇ O)R 7 , —O(C ⁇ O)N(R 7 )(R 7 ), and —N(R 7 )(C ⁇ O)OR 7 ;
  • R 1 and R 2 are not hydrogen;
  • R 3 is selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, and heterocycloalkyl, wherein R 3 other than hydrogen may be optionally substituted with one or more substituents that do not adversely affect the desired reaction, for example a substituent selected from oxo, halo, cyano, azido, nitro, R 7 , —OR 7 , —N(R 7 )(R 7 ), —(C ⁇ O)R 7 , —(C ⁇ O)OR 7 , —(C ⁇ O)N(R 7 )(R 7 ), —O(C ⁇ O)R 7 , —N(R 7 )(C ⁇ O)R 7 , —O(C ⁇ O)N(R 7 )(R 7 ), and —N(,R 7 )(C ⁇ O)OR 7 ; or
  • R 1 and R 2 or R 2 and R 3 are taken together with the carbons to which they are attached to form a cycloalkyl ring or an heterocycloalkyl ring, wherein each cycloalkyl or heterocycloalkyl ring can be optionally substituted with one or more substituents that do not adversely affect the desired reaction, for example a substituent selected from oxo, halo, cyano, azido, nitro, R 7 , —OR 7 , —N(R 7 )(R 7 ), —(C ⁇ O)R 7 , —(C ⁇ O)OR 7 , —(C ⁇ O)N(R 7 )(R 7 ), —O(C ⁇ O)R 7 , —N(R 7 )(C ⁇ O)R 7 , —O(C ⁇ O)N(R 7 )(R 7 ), and —N(R 7 )(C ⁇ O)OR 7 ;
  • R 4 is independently selected at each occurrence from alkyl and cycloalkyl
  • the organic promoter is selected from:
  • R 5 is independently selected from hydrogen, halo, cyano, azido, nitro, R 7 , —OR 7 , —N(R 7 )(R 7 ), —(C ⁇ O)R 7 , —(C ⁇ O)OR 7 , —(C ⁇ O)N(R 7 )(R 7 ), —O(C ⁇ O)R 7 , —N(R 7 )(C ⁇ O)R 7 , —(C ⁇ O)N(R 7 )(R 7 ), and —N(R 7 )(C ⁇ O)OR 7 ;
  • n 1, 2, 3, or 4;
  • R 6 and R 6′ are independently selected from —O(C ⁇ O)R 7 , —O(SO 2 )(R 7 ), hydroxyl, and azido;
  • R 7 is independently selected at each occurrence from hydrogen, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, and trialkylsilyl, each of which R 7 other than hydrogen may be optionally substituted with one or more substituents that do not adversely affect the desired reaction, for example a substituent selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, amino, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido, acyl, acyloxy, carboxyl, carboxyl ester, alkanoyl, carboxamide, haloalkyl, and haloalkoxy; or
  • two R 7 groups may be brought together with the atoms to which they are attached to from a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, each of which ring may be optionally substituted with one or more substituents that do not adversely affect the desired reaction, for example a substituent selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, amino, alkylatmino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido, acyl, acyloxy, carboxyl, carboxyl ester, alkanoyl, carboxamide, haloalkyl, and haloalkoxy;
  • R 8 and R 8′ are independently selected from hydrogen, halo, cyano, azido, nitro, R 7 , —OR 7 , —N(R 7 )(R 7 ), —(C ⁇ O)R 7 , —(C ⁇ O)OR 7 , —(C ⁇ O)N(R 7 )(R 7 ), —O(C ⁇ O)R 7 , —N(R 7 )(C ⁇ O)R 7 , —O(C ⁇ O)N(R 7 )(R 7 ), and —N(R 7 )(C ⁇ O)OR 7 ; or
  • R 8 and R 8′ may be brought together with the carbon to which they are attached to form a cycloalkyl or heterocycloalkyl ring, each of which ring may be optionally substituted with one or more substituents that do not adversely affect the desired reaction, for example a substituent selected from oxo, halo, cyano, azido, nitro, R 7 , —OR 7 , —N(R 7 )(R 7 ), —(C ⁇ O)R 7 , —(C ⁇ O)OR 7 , —(C ⁇ O)N(R 7 )(R 7 ), —O(C ⁇ O)R 7 , —N(R 7 )(C ⁇ O)R 7 , —O(C ⁇ O)N(R 7 )(R 7 ), and —N(R 7 )(C ⁇ O)OR 7 ; or
  • R 8 and R 8′ are brought together to form an oxo or imino group
  • R 9 is aryl or heteroaryl, for example phenyl, pyridyl, pyrazinyl, or quinolinyl, wherein R 9 may be optionally substituted with one or more substituents that do not adversely affect the desired reaction, for example a substituent selected from oxo, halo, cyano, azido, nitro, R 7 , —OR 7 , —N(R 7 )(R 7 ), —(C ⁇ O) R 7 , —(C ⁇ O)OR 7 , —(C ⁇ O)N(R 7 )(R 7 ), —O(C ⁇ O) —N(R 7 )(C ⁇ O)R 7 , —O(C ⁇ O)N(R 7 )(R 7 ), and —N(R 7 )(C ⁇ O)OR 7 ; and
  • the hydrogen bond donor is water and optionally a second hydrogen bond donor selected from formic acid, an alkylcarboxylic acid, a (cycloalkyl)carboxylic acid, a (heteroalkyl)carboxylic acid, a (heterocycloalkyl)carboxylic acid, an arylcarboxylic acid, an (heteroaryl)carboxylic acid, sulfuric acid, an alkylsulfonic acid, a (cycloalkyl)sulfonic acid, a (heteroalkyl)sulfonic acid, a (heterocycloalkyl)sulfonic acid, a arylsulfonic acid, and a (heteroaryl)sulfonic acid, each of which second hydrogen bond donor other than formic acid and sulfuric acid can be optionally substituted with one or more substituents that do not adversely affect the desired reaction, for example a substituent selected from alkyl, heteroalkyl, cycloal
  • the organic azide formed by the process shown in Scheme I produces the anti-Markovnikov addition product or comprises at least about 50% or more of the anti-Markovnikov addition product.
  • a process for the synthesis of azide-containing oligomers or polymers from simple olefin starting materials.
  • the azide-substituted oligomeric or polymeric compounds that are formed by this process are useful in the synthesis of new materials, such as new polymers for use in medical devices, or in bioconjugation reactions that may lead to new drug delivery methods, for example biologic-polymer-drug conjugates.
  • This oligomerization or polymerization method allows for the preparation of these materials without metal contamination, again allowing ready use in biological systems without concern for toxic contamination.
  • a process for the synthesis of an azide-containing oligomer or polymer comprising mixing an olefin, a silylazide, a hydrogen bond donor, and an organic promoter, wherein the olefin is substituted with at least one electron withdrawing group, such that an azide-containing oligomer or polymer is formed.
  • a process is provided for the synthesis of an oligomer or polymer of Formula V comprising mixing an olefin of Formula IV, a silyl azide of Formula II, an organic promoter, and a hydrogen bond donor such that an oligomer or polymer of Formula V is formed.
  • a process for the synthesis of an azide-containing oligomer or polymer is provided as illustrated in Scheme 2:
  • R 4 , R 7 , the organic promoter, and the hydrogen bond donor are as defined above;
  • R 10 , R 11 , and R 12 are independently selected from hydrogen, halogen, cyano, —(C ⁇ O)R 7 , —(C ⁇ O)OR 7 , —(C ⁇ O)N(R 7 )(R 7 ), alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of R 10 , R 11 , and R 12 other than hydrogen, halogen, or cyano may be optionally substituted with one or more substituents that do not adversely affect the desired reaction, for example a substituent selected from oxo, halo, cyano, azido, nitro, R 7 , —OR 7 , —N(R 7 )(R 7 ), —(C ⁇ O) R 7 , —(C ⁇ O)OR 7 , —(C ⁇ O)N(R 7 )(R 7 ), —O(C ⁇ O)R 7 , —N(
  • R 10 and R 11 or R 11 and R 12 may be brought together with the carbons to which they are attached to form a cycloalkyl ring or a heterocycloalkyl ring, each of which cycloalkyl or heterocycloalkyl ring may be optionally substituted with one or more substituents that do not adversely affect the desired reaction, for example a substituent selected from oxo, halo, cyano, azido, nitro, R 7 , —OR 7 , —N(R 7 )(R 7 ), —(C ⁇ O)R 7 , —(C ⁇ O)OR 7 , —(C ⁇ O)N(R 7 )(R 7 ), —(C ⁇ O)R 7 , —N(R 7 )(C ⁇ O)R 7 , —O(C ⁇ O)N(R 7 )(R 7 ), and —N(R 7 )(C ⁇ O)OR 7 ;
  • R 10 and R 11 may be brought together with the carbons to which they are attached to form a cycloalkyl ring or a heterocycloalkyl ring, each of which cycloalkyl or heterocycloalkyl ring may be optionally substituted with one or more substituents that do not adversely affect the desired reaction, for example a substituent selected from oxo, halo, cyano, azido, nitro, R 7 , —OR 7 , —N(R 7 )(R 7 ), —(C ⁇ O)R 7 , —(C ⁇ O)OR 7 , —(C ⁇ O)N(R 7 )(R 7 ), —O(C ⁇ O)R 7 , —N(R 7 )(C ⁇ O)R 7 , —O(C ⁇ O)N(R 7 )(R 7 ), and —N(R 7 )(C ⁇ O)OR 7 ;
  • R 13 is selected from cyano, nitro, —(C ⁇ O)R 7a , —(C ⁇ O)OR 7a , and —(C ⁇ O)N(R 7a )(R 7b );
  • R 7a and R 7b are independently selected at each occurrence from hydrogen, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, and trialkylsilyl, each of which R 7a and R 7b other than hydrogen may be optionally substituted with one or more substituents that do not adversely affect the desired reaction, for example a substituent selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, amino, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido, acyl, acyloxy, carboxyl, carboxyl ester, alkanoyl, carboxamide, haloalkyl, and haloalkoxy; or
  • R 7a and R 7b may be brought together with the atoms to which they are attached to form a cycloalkyl or heterocycloalkyl ring, each of which ring may be optionally substituted with one or more substituents that do not adversely affect the desired reaction, for example a substituent selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, amino, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido, acyl, acyloxy, carboxyl, carboxyl ester, alkanoyl, carboxamide, haloalkyl, and haloalkoxy; or
  • R 10 and R 7a may be brought together with the atoms to which they are attached to form a cycloalkyl or heterocycloalkyl ring, each of which ring may be optionally substituted with one or more substituents that do not adversely affect the desired reaction, for example a substituent selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, amino, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido, acyl, acyloxy, carboxyl, carboxyl ester, alkanoyl, carboxamide, haloalkyl, and haloalkoxy; and
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25.
  • the olefin is a terminal olefin. In other aspects, the olefin is an asymmetric internal olefin. In other aspects, the olefin is a trisubstituted olefin. In some embodiments, for example those represented in Scheme 2, the olefin contains an electron-withdrawing substituent.
  • the hydrogen bond donor is water. In another aspect, the hydrogen bond. donor is water and a second hydrogen bond donor. In one embodiment, the second hydrogen bond donor is trifluoroacetic acid. In some embodiments, the hydrogen bond donor is a chiral hydrogen bond donor.
  • the process described herein is carried out in an organic solvent, a mixture of water and an organic solvent, or a mixture of two or more organic solvents.
  • exemplary solvents include acetone, ethyl acetate (EtOAc), dichloromethane (CH 2 Cl 2 ), acetonitrile (MeCN), 1,2-dichloroethane (DCE), nitromethane, hexanes, pentane, toluene, benzene, petroleum ether, 2-butanone, chlorobenzene, chloroform (CHCl 3 ), cyclohexane, heptane, o-xylene, m-xylene, p-xylene, and combinations thereof.
  • the solvent is selected from ethyl acetate (EtOAc), dichloromethane (Ch 2 Cl 2 ), or chloroform (CHCl 3 ).
  • the solvent is ethyl acetate (EtOAc).
  • the solvent is dichloromethane (CH 2 Cl 2 ).
  • the solvent is chloroform (CHCl 3 ).
  • a compound used in or formed by the processes described herein can have at least one isotopic substitution.
  • a compound used in or formed by the processes described herein can have at least one deuterium atom.
  • the inclusion of deuterium can affect the rate of a reaction or the stability of the final product, among other things. If the product is a pharmaceutical agent, substitution with deuterium can be used in metabolic profiling.
  • a process is provided for the synthesis of a beta-deuteroalkyl azide of Formula VI as illustrated in Scheme 3:
  • R 1 , R 2 , R 3 , R 4 , and the organic promoter are defined as above;
  • the deuterium bond donor consists of deuterium oxide and optionally a deuterated acid selected from trifluoroacetic acid-d, acetic acid-d 4 , trifluoromethanesulfonic acid-d, methanesulfonic acid-d 4 , and formic acid-d 2 .
  • the deuterium is completely incorporated into the product of Formula VIII.
  • the deuterium is partially incorporated into the product of Formula VIII, for example, about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.9%, 99.99%, or 99.999% incorporated.
  • a mixture of deuterium oxide and water is used instead of pure deuterium oxide in the reaction shown in Scheme 3.
  • R 4 , R 10 ,R 11 , R 12 , R 13 , the organic promoter, and the deuterium bond donor are defined as above.
  • the deuterium is completely incorporated into the product of Formula XI.
  • the deuterium is partially incorporated into the product of Formula. XI, for example, about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.9%, 99.99%, or 99.999% incorporated.
  • a mixture of deuterium oxide and water is used instead of pure deuterium oxide in the reaction shown in Scheme 4.
  • R 4 , R 5 , R 7 , Z, and m are defined as above;
  • R 14 and R 14′ are selected from —O(C ⁇ O)R 7 and —O(SO 2 )(R 7 ).
  • processes are also provided for the use of the azide-containing product of the inventive process described herein with an alkyne to make a 1,2,3-triazole, for example using an azide-alkyne cycloaddition, in the presence or absence of copper.
  • a ligand can be added to a biomolecule via the reaction described herein to create an organic azide derivative of an unsaturated starting material, which is then reacted with an alkyne-modified biomolecule.
  • An organic azide formed from an olefin using the processes described herein can be conjugated to an alkyne-containing modified biomolecule using an azide-alkyne cycloaddition reaction.
  • processes are also provided for the use of the azide-containing product of the inventive process described herein with an alkyne to make a 1,2,3-triazole, for example using an azide-alkyne cycloaddition, in the presence or absence of copper.
  • a ligand can be added to a biomolecule via the reaction described herein to create an organic azide derivative of an unsaturated starting material, which is then reacted with an alkyne-modified biomolecule.
  • An organic azide formed from an olefin using the processes described herein can be conjugated to an alkyne-containing modified biomolecule using an azide-alkyne cycloaddition reaction.
  • a process for the conjugation of an organic ligand molecule to a modified biomolecule comprising:
  • a process for the conjugation of an organic ligand molecule to a modified biomolecule comprising:
  • a process for the conjugation of an azide-containing oligomer or polymer formed from an organic molecule containing an alkenyl group to a modified biomolecule, wherein the modified biomolecule contains an alkynyl group comprising:
  • the biomolecule can be, in non-limiting embodiments, a protein, peptide, a nucleoside, nucleotide, polynucleotide, such as a polydeoxyribonucleotide or a polyribonucleotide, antibody, hormone, enzyme, structural protein, aptamer, m-RNA, cDNA, cell, including a lymphocyte, signaling agent, a sugar, a monosaccharide or polysaccharide, or a lipid or lipid-like molecule.
  • the organic molecule may be a substrate, an inhibitor, a drug, a mediator of signaling, a fluorescent probe, or any other organic compound that has or can be modified to have an olefin-containing group that may be useful to conjugate with a biomolecule for any purpose.
  • Step (c) in any embodiments of the bioconjugation process can be performed ex vivo, in vitro, or in vivo depending on the desired application.
  • Non-limiting aspects of the present invention include:
  • a process for the synthesis of a deuterated azide-containing oligomer or polymer of Formula XI by mixing an olefin of IV, a silyl azide of Formula II, an organic promoter, and a deuterium bond donor until the azide-containing oligomer or polymer of Formula XI is formed;
  • the compounds in any of the Formulas described herein may be in the form of a racemate, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, tautomer, N-oxide, or other isomer, such as a rotamer, as if each is specifically described unless specifically excluded by context.
  • a dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example,
  • Alkyl is a branched or straight chain saturated aliphatic hydrocarbon group.
  • the alkyl group contains from about 1 to about 50 carbon atoms, more generally from 1 to about 36 carbon atoms, from 1 to about 12 carbon atoms, from 1 to about 8 carbon atoms, from 1 to about 6 carbon atoms, or from 1 to about 4 carbon atoms.
  • the alkyl is C 1 -C 2 , C 1 -C 3 , or C 1 -C 4 , C 1 -C 5 , C 1 -C 6 , C 1 -C 7 , C 1 -C 8 , C 1 -C 9 , C 1 -C 10 .
  • C 1 -C 6 alkyl indicates a straight chain or branched alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these are described as an independent species.
  • C 1 -C 4 alkyl indicates a straight or branched alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentance, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane.
  • the alkyl group is optionally substituted as defined herein.
  • alkyl is a C 1 -C 10 alkyl, C 1 -C 9 alkyl, C 1 -C 8 alkyl, C 1 -C 7 alkyl, C 1 -C 6 alkyl, C 1 -C 5 alkyl, C 1 -C4alkyl, C 1 -C3alkyl, C 1 -C2alkyl, or C 1 -C1alkyl.
  • alkyl has one carbon
  • alkyl has two carbons.
  • alkyl has three carbons.
  • alkyl has four carbons.
  • alkyl has five carbons.
  • alkyl has six carbons.
  • alkyl include: methyl, ethyl, propyl, butyl, pentyl, and hexyl.
  • alkyl examples include: isopropyl, isobutyl, isopentyl, and isohexyl.
  • alkyl examples include: sec-butyl, sec-pentyl, and sec-hexyl.
  • alkyl examples include: tert-butyl, tert-pentyl, and tert-hexyl.
  • alkyl include: neopentyl, 3-pentyl, and active pentyl.
  • alkyl is “substituted alkyl”
  • Heteroalkyl refers to an alkyl group as defined herein that contains at least one heteroatom, for example nitrogen, oxygen, sulfur, phosphorous, boron, or silicon, in place of a carbon atom at a position other than at the point of attachment.
  • heteroalkyl also includes groups that contain unsaturation between the heteroatom and a neighboring carbon in such a manner that results in the formation of a stable moiety, for example a —C ⁇ N-moiety.
  • Cycloalkyl is a saturated group containing all carbon rings and from 3 to 50 carbon atoms (“C 3 -C 50 cycloalkyl”) and zero heteroatoms in a monocyclic or polycyclic (e.g. bicyclic or tricyclic) non-aromatic ring system.
  • a cycloalkyl group has 3 to 14 ring atoms (“C 3 -C 14 cycloalkyl”).
  • a cycloalkyl group has 3 to 10 ring atoms (“C3-C 10 cycloalkyl”).
  • a cycloalkyl group has 3 to 9 ring atoms (“C 3 -C9cycloalkyl”).
  • a cycloalkyl group has 3 to 8 ring atoms (“C 3 -C 8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 7 ring atoms (“C 3 -C 7 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring atoms (“C 3 -C 6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring atoms (“C 4 -C 6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring atoms (“C 5 -C 6 cycloalkyl”).
  • a cycloalkyl group has 5 to 10 ring atoms (“C 5 -C 10 cycloalkyl”).
  • C 5 -C 10 cycloalkyl ring atoms
  • Exemplary C 3 -C 10 cycloalkyl groups include, without limitation, cyclopropyl (C 3 ), cyclobutyl (C 4 ), cyclopentyl (C 5 ), cyclohexyl (C 6 ), cycloheptyl (C 7 ), cyclooctyl (C 8 ), cyclononyl (C 9 ), cyclodecenyl (C 10 ), and the like.
  • a cycloalkyl group may be a bicyclic alkyl group, for example a spirocyclic alkyl group, a fused bicyclic alkyl group, or a bridged bicyclic alkyl group.
  • “cycloalkyl” also includes ring systems wherein the cycloalkyl ring, as defined above, is fused with one heterocycloalkyl, aryl, or heteroaryl ring wherein the point of attachment is on the cycloalkyl ring, and in such instances, the number of carbon atoms continue to designate the number of carbons in the cycloalkyl ring system.
  • the cycloalkyl group is optionally substituted as defined herein.
  • cycloalkyl is a C 3 -C 8 cycloalkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl, C 3 -C 5 cycloalkyl, C 3 -C 4 cycloalkyl, C 4 -C 8 -cycloalkyl, C 5 -C 8 cycloalkyl, or C 6 -C 8 cycloalkyl.
  • cycloalkyl has three carbons.
  • cycloalkyl has four carbons.
  • cycloalkyl has five carbons.
  • cycloalkyl has six carbons.
  • cycloalkyl has seven carbons.
  • cycloalkyl has eight carbons.
  • cycloalkyl has nine carbons.
  • cycloalkyl has ten carbons.
  • cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.
  • cycloalkyl include dihydro-indene and tetrahydronaphthalene wherein the point of attachment for each group is on the cycloalkyl ring.
  • cycloalkyl is a “substituted cycloalkyl”
  • heterocycloalkyl refers to a cycloalkyl group as defined herein that contains at least one heteroatom, for example nitrogen, oxygen, sulfur, phosphorous, boron, or silicon, in place of a carbon atom.
  • Heterocycloalkyl groups comprise monocyclic 3-8 membered rings, as well as 5-16 membered bicyclic ring systems (which can include bridged, fused, and spiro-fused bicyclic ring systems). It does not include rings containing —O—O, —O—S—, and —S—S-portions.
  • heterocycloalkyl also includes groups that contain unsaturation between the heteroatom and a neighboring carbon in such a manner that results in the formation of a stable moiety, for example a —C ⁇ N-moiety.
  • heterocycloalkyl also includes ring systems wherein the cycloalkyl ring, as defined above, is fused with one cycloalkyl, aryl, or heteroaryl ring wherein the point of attachment is on the heterocycloalkyl ring, and in such instances, the number of atoms continue to designate the number of atoms in the heterocycloalkyl ring system.
  • the cycloalkyl group is optionally substituted as defined herein.
  • the heterocycloalkyl group is optionally substituted as defined herein.
  • heterocycloalkyl groups include saturated 3- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms; saturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms; and saturated saturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms.
  • heterocycloalkyl groups include aziridinyl, oxiranyl, thiiranyl, azetidinyl, 1,3-diazetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, 2-pyrazolinyl, 2-imidazolinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydrothienyl, pipetidinyl, piperazinyl, 1,2-oxathiolanyl, 1,3-oxathiolanyl, tetrahydropyranyl, 1,3-dioxanyl, thianyl, 1,3-dithianyl, 1,4-dithianyl, 1,3,5-trithianyl, morpholinyl, thiomorpholinyl, pyrrolizidinyl, indolinyl,
  • heterocycloalkyl refers to a cyclic ring with one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.
  • heterocycloalkyl refers to a cyclic ring with one nitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.
  • heterocycloalkyl refers to a cyclic ring with two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms.
  • heterocycloalkyl refers to a cyclic ring with one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.
  • heterocycloalkyl refers to a cyclic ring with one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms.
  • heterocycloalkyl examples include aziridine, oxirane, thiirane, azetidine, 1,3-diazetidine, oxetane, and thietane.
  • heterocycloalkyl examples include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine, and imidazollidine.
  • heterocycloalkyl examples include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane.
  • heterocyclalkyl examples include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.
  • heterocyoalkyl examples include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the heterocyclic ring.
  • heterocycloalkyl is a “heterocycloalkyl” group.
  • heterocycloalkyl also include:
  • heterocycloalkyl examples include:
  • heterocycloalkyl examples include:
  • heterocycloalkyl also include:
  • heterocycloalkyl also include:
  • heterocycloalkyl examples include:
  • heterocycloalkyl examples include:
  • heterocycloalkyl is “substituted heterocycloalkyl”.
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic system (“C 6 -C 14 aryl”).
  • an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl goup has 10 ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl).
  • an aryl group has 14 ring carbon atoms (“C 14 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more cycloalkyl or heterocycloalkyl groups wherein the point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • the one or more fused cycloalkyl or heterocycloalkyl groups can be 4 to 7 or 5 to 7-membered cycloalkyl or heterocycloalkyl groups that optionally contain 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorous, sulfur, silicon, and boron.
  • aryl groups are pendant.
  • An example of a pendant ring is a phenyl group substituted with a phenyl group.
  • the aryl group is optionally substituted as defined herein.
  • aryl is a 6 carbon aromatic group (phenyl).
  • aryl is a 10 carbon aromatic group (napthyl).
  • aryl is a 6 carbon aromatic group fused to a heterocycle wherein the point of attachment is the aryl ring.
  • aryl include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the aromatic ring.
  • aryl is a 6 carbon aromatic group fused to a cycloalkyl wherein the point of attachment is the aryl ring
  • aryl include dihydro-indene and tetrahydronaphthalene wherein the point of attachment for each group is on the aromatic ring.
  • aryl is “substituted aryl”.
  • heteroaryl denotes aryl ring systems that contain one or more heteroatoms selected from O, N, and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quatemized.
  • Examples include, but are not limited to: unsaturated 5- to 6-membered heterotnonocyclyl groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, and triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, and 2H-1,2,3-triazolyl]; unsaturated 5-to 6-membered heteromonocyclic groups containing an oxygen group, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5- to 6-membered heteromonocyclic groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen
  • Heteroaryl also refers to polycyclic aromatic ring systems containing heteroatoms within the ring, for example, 1,4-dihydropyrollo[3,2-b]pyrrolyl, 1,6-dihydropyrrolo[2,3-b]pyrrolyl, 6H-furo[2,3-b]pyrrolyl, 4H-furo[3,2-b]pyrrolyl, 4H-thieno[3,2-b]pyrrolyl, 6H-thieno[2,3-b]pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, benzimidazolyl, 7-azaindolyl, 6-azaindolyl, 5-azaindolyl, 4-azaindolyl, 7-azaindazolyl, pyrazole[1,5-a]pyrimidinyl, purinyl, benzofuryl, isobenzofuryl, benzo[c]thien
  • heteroaryl groups include azepinyl, 1,2-diazepinyi, 1,3-diazepinyl, 1,4-diazepinyl, thiepinyl, 1,4-thiazepinyl, and azocinyl.
  • “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more cycloalkyl or heterocycloalkyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of atoms continue to designate the number of atoms in the heteroaryl ring system.
  • the one or more fused cycloalkyl or heterocycloalkyl groups can be 4 to 7 or 5 to 7-membered cycloalkyl or heterocycloalkyl groups that optionally contain 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorous, sulfur, silicon, and boron.
  • aryl groups are pendant.
  • heteroaryl is a 5 membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms.
  • Non-limiting examples of 5 membered “heteroaryl” groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole.
  • heteroaryl is a 6 membered aromatic group containing 1, 2, or 3 nitrogen atoms i.e, pyridinyl pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).
  • Non-limiting examples of 6 membered “heteroaryl” groups with 1 or 2 nitrogen atoms include:
  • heteroaryl is a 9 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.
  • heteroaryl groups that are bicyclic include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzooxazole, and benzothiazole.
  • heteroaryl groups that are bicyclic include:
  • heteroaryl groups that are bicyclic include:
  • heteroaryl groups that are bicyclic include:
  • heteroaryl is a 10 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.
  • heteroaryl groups that are bicyclic include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.
  • heteroaryl groups that are bicyclic include:
  • heteroaryl is “substituted heteroaryl”
  • a group described herein that can be substituted with 1, 2, or 4 substituents is substituted with two substituents.
  • a group described herein that can be substituted with 1, 2, 3, or 4 substituents is substituted with three substituents.
  • a group described herein that can be substituted with 1, 2, 3, or 4 substituents is substituted with four substituents.
  • solvate refers to a molecular complex of a compound of the present invention (including a salt thereof) with one or more solvent molecules.
  • solvent are water, ethanol, dimethyl sulfoxide, acetone, and other common organic solvents.
  • hydrate refers to a molecular complex comprising a compound as described herein and water.
  • Solvates in accordance with this disclosure include those wherein the solvent may be isotopically substituted, e.g. D 2 O, d 6 -acetone, and d 6 -DMSO.
  • a solvate can be in a liquid or solid form.
  • any compound used in or formed by the processes described herein may be modified by making inorganic or organic acid or base addition salts thereof.
  • the salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical processes. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reactive free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like
  • salts of the present compounds further include solvates of the compound and the compound salts.
  • salts as described herein include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the salts described herein include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, make, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)n-COOH where n is 0-4, and the like, or using a different acid that produces the same counterion.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric,
  • the process of the present invention involves an olefin reactant.
  • the olefin reactant is an asymmetric olefin, i.e., the two substituents attached to one of the olefinic carbons are not the same as the two substituents attached to the other olefinic carbon.
  • the olefin reactant contains a terminal olefin, i.e., one of the olefinic carbons has two hydrogen atoms, and therefore no carbon atoms, as substituents.
  • the olefin reactant contains a non-terminal olefin, meaning that each olefinic carbon has at least one non-hydrogen substituent.
  • the olefin reactant is a tri-substituted olefin containing three non-hydrogen substituents.
  • the olefin reactant is a compound of Formula I:
  • R 1 , R 2 , and R 3 are defined as above.
  • Non-limiting examples of olefin reactants of Formula I that may be used in the present process include:
  • Non-limiting examples of olefin reactants of Formula I that may be used in the present process include:
  • olefin reactants of Formula I include
  • the olefin reactant is an alkene containing an electron-withdrawing group, for example an enone, an acrolein, an acrylate, an acrylamide, or an acrylonitrile.
  • the olefin reactant is a compound of Formula IV:
  • R 10 ,R 11 , R 12 and R 13 are defined as above.
  • the olefin reactant is a compound of Formula IVa:
  • R 10 , R 11 , R 12 , and R 7a are defined as above.
  • the olefin reactant is a compound of Formula IVb:
  • R 10 , R 11 , R 12 ,and R 7a are defined as above.
  • the olefin reactant is a compound of Formula IVc:
  • R 10 , R 11 , R 12 ,and R 7a and R 7b are defined as above.
  • the olefin reactant is a compound of Formula IVd:
  • R 10 , R 11 and R 12 are defined as above.
  • the olefin reactant is a compound of Formula IVe or Formula IVf:
  • R 11 and R 12 are defined as above.
  • Non-limiting examples of the olefin reactant of Formula IV include:
  • olefin reactant of Formula IV include:
  • the process of the present invention also includes a silylazide reactant.
  • the silylazide reactant is a trialkylazide.
  • the silylazide reactant is a compound of Formula II:
  • R 4 is independently selected at each occurrence from alkyl or cycloalkyl
  • two R 4 groups may be brought together with the silicon to which they are attached to form a cycloalkyl ring.
  • the silylazide reactant is trimethylsilylazide.
  • the silylazide reactant is triethylsilylazide.
  • the silylazide reactant is (tert-butyldimethylsilyl)azide.
  • the process of the present invention also includes an organic promoter.
  • the organic promoter is a compound of Formula IX or Formula X:
  • R 5 , R 6 , R 6′ , R 8 , R 8′ , and m are defined as above.
  • the organic promoter is a compound of Formula IXa:
  • R 5 , Z and m are defined as above.
  • the organic promoter is a compound of Formula IXb:
  • R 7 is an electron withdrawing substituent, for example trifluoromethyl or trichloromethyl.
  • the organic promoter is a compound of Formula IXc:
  • R 7 is an electron withdrawing substituent, for example trifluoromethyl or trichloromethyl.
  • the organic promoter is a compound of Formula IXd:
  • R 5 , Z and m are defined as above.
  • the organic promoter is a compound of the formula
  • the organic promoter is a compound of the formula
  • the organic promoter is a compound of the formula
  • the organic promoter is a compound of the formula
  • the organic promoter is a compound of the formula
  • the organic promoter is a compound of Formula Xa:
  • R 5 , R 6 , R 6′ , and Z are as defined above;
  • o 1, 2, 3, 4, or 5.
  • the organic promoter is a compound of Formula Xb:
  • R 7 is an electron withdrawing substituent, for example trifluoromethyl or trichloromethyl.
  • the organic promoter is a compound of the formula Xc:
  • R 5 , Z, and o are defined as above.
  • the organic promoter is a compound of the formula
  • the organic promoter is a compound of the formula
  • R 4 , R 5 , R 14 , R 14′ , Z, and m are defined as above.
  • Non-limiting examples of compounds of Formula VII include:
  • the above molecules of Formula VII can be modified to have mixed alkyl groups on the silicon, for example two ethyl groups and one methyl group, and to have substituents on any apparent phenyl group, for example a methyl, methoxy, trifluoromethyl, chloro, or fluoro group.
  • R 4 , R 5 , R 14 , Z, and m are defined as above.
  • Non-limiting examples of compounds of Formula VIII include:
  • the above molecules of Formula VII can be modified to have mixed alkyl groups on the silicon, for example two ethyl groups and one methyl group, and to have substituents on any apparent phenyl group, for example a methyl, methoxy, trifluoromethyl, chloro, or fluoro group,
  • the process of the present invention includes the use of a hydrogen bond donor.
  • the hydrogen bond donor is water.
  • the hydrogen bond donor comprises water and an optional second hydrogen bond donor.
  • the second hydrogen bond donor is selected from an organic acid or a mineral acid.
  • the second hydrogen bond donor is formic acid.
  • the second hydrogen bond donor is an alkylcarboxylic acid optionally substituted with one or more substituents selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, heterocycloalkoxy, atyloxy, heteroaryloxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, heteroarylamino, alkylsufonamino, arylsufonamino, alkylimino, arylimino, alkylsulfonimino, arylsulfonitnino, hydroxyl, halo, sulthydryl, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, guanidine, urei
  • the second hydrogen bond donor is a (cycloalkyl)carboxylic acid optionally substituted with one or more substituents selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, atyloxyamino, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido, acyl, acyloxy, carboxyl, carboxyl ester, alkanoyl, carboxamide, haloalkyl, and haloalkoxy.
  • substituents selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, atyloxyamino, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido, acy
  • the second hydrogen bond donor is a (heteroalkyl)carboxylic acid optionally substituted with one or more substituents selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxyami no, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido, acyl, acyloxy, carboxyl, carboxyl ester, alkanoyl, carboxamide, haloalkyl, and haloalkoxy.
  • substituents selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxyami no, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido, acyl
  • the second hydrogen bond donor is a (heterocycloalkyl)carboxylic acid optionally substituted with one or more substituents selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxyamino, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido, acyl, acyloxy, carboxyl, carboxyl ester, alkanoyl, carboxamide, haloalkyl, and haloalkoxy.
  • substituents selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxyamino, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido
  • the second hydrogen bond donor is an arylcarboxylic acid optionally substituted with one or more substituents selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxyamino, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido, acyl, acyloxy, carboxyl, carboxyl ester, alkanoyl, carboxamide, haloalkyl, and haloalkoxy.
  • substituents selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxyamino, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido, acyl, acyl
  • the second hydrogen bond donor is a (heteroaryl)carboxylic acid optionally substituted with one or more substituents selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxyamino, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido, acyl, acyloxy, carboxyl, carboxyl ester, alkanoyl, carboxamide, haloalkyl, and haloalkoxy.
  • substituents selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxyamino, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido, acy
  • the second hydrogen bond donor is sulfuric acid.
  • the second hydrogen bond donor is an alkylsulfonic acid optionally substituted with one or more substituents selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxyamino, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido, acyl, acyloxy, carboxyl, carboxyl ester, alkanoyl, carboxamide, haloalkyl, and haloalkoxy.
  • the second hydrogen bond donor is methanesulfonic acid.
  • the second hydrogen bond donor is trifluoromethylsulfonic acid.
  • the second hydrogen bond donor is an (cycloalkyl)sulfonic acid optionally substituted with one or more substituents selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxyamino, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido, acyl, acyloxy, carboxyl, carboxyl ester, alkanoyl, carboxamide, haloalkyl, and haloalkoxy,
  • substituents selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxyamino, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido, acyl
  • the second hydrogen bond donor is a (heteroalkyl)sulfonic acid optionally substituted with one or more substituents selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxyamino, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido, acyl, acyloxy, carboxyl, carboxyl ester, alkanoyl, carboxamide, haloalkyl, and haloalkoxy.
  • substituents selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxyamino, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido,
  • the second hydrogen bond donor is a (heterocycloalkyl)sulfonic acid optionally substituted with one or more substituents selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxyamino, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido, acyl, acyloxy, carboxyl, carboxyl ester, alkanoyl, carboxamide, haloalkyl, and haloalkoxy.
  • substituents selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxyamino, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido
  • the second hydrogen bond donor is an arylsulfonic acid optionally substituted with one or more substituents selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxyamino, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido, acyl, acyloxy, carboxyl, carboxyl ester, alkanoyl, carboxamide, haloalkyl, and haloalkoxy.
  • substituents selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxyamino, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido, acyl, acyl
  • the second hydrogen bond donor is a (heteroaryl)sulfonic acid optionally substituted with one or more substituents selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxyamino, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido, acyl, acyloxy, carboxyl, carboxyl ester, alkanoyl, carboxamide, haloalkyl, and haloalkoxy.
  • substituents selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxyamino, alkylamino, dialkylamino, hydroxyl, halo, acylamino, aminoacyl, cyano, nitro, azido, acy
  • the hydrogen bond donor is a chiral hydrogen bond donor.
  • Representative examples of chiral hydrogen bond donors are described in Doyle. A. G. and Jacobsen, L. N. Chemical Reviews 2007, 107 , 5713, incorporated herein by reference in its entirety.
  • the absolute and relative amounts of the various components in the inventive process for making nitrogen-containing organic compounds can vary as desired to achieve the desired goal.
  • the benziodoxole is typically present in an amount between about 5 and about 50 mol %) relative to the amount of olefin reactant. In one embodiment, the benziodoxole is present in an amount between about 5 and about 30 mol % relative to the amount of olefin reactant. In another embodiment, the benziodoxole is present in an about between about 7 and about 20 mol % relative to the amount of olefin reactant.
  • the benziodoxole is present in at least about 5 mol %, at least about 6 mol %, at least about 7 mol %, at least about 8 mol %, at least about 9 mol %, at least about 10 mol %, at least about 15 mol %, at least about 20 mol %, at least about 25 mol %, at least about 30 mol %, at least about 35 mol %, at least about 40 mol %, or at least about 50 mol %, relative to the amount of olefin reactant.
  • the silylazide is typically present in an amount between about 1.8 and about 3.0 equivalents relative to the amount of olefin reactant. In one embodiment, the silylazide is present in an amount between about 2.0 and about 2.5 equivalents relative to the amount of olefin reactant. In one embodiment, the silylazide is present in at least about 1.8 equivalents, 1.9 equivalents, 2.0 equivalents, 2.1 equivalents, 2.2 equivalents, 2.3 equivalents, 2.4 equivalents, 2.5 equivalents, 2.6 equivalents, 2.7 equivalents, 2.8 equivalents, 2.9 equivalents, or 3.0 equivalents relative to the amount of olefin reactant. In one embodiment, the silylazide is present in an at least about the sum of the equivalents of the hydrogen bond donor and twice the equivalents of the benziodoxole.
  • water is typically present in an amount between about 0.6 to about 1.5 equivalents relative to the amount of olefin reactant. In some embodiments, water is present in an amount between about 0.8 to about 1.2 equivalents relative to the amount of olefin reactant. In some embodiment, water is present in at least about 0.6 equivalents, 0.7 equivalents, 0.8 equivalents, 0.9 equivalents, 1.0 equivalents, 1.1 equivalents, 1.2 equivalents, 1.3 equivalents, 1.4 equivalents, or 1.5 equivalents relative to the amount of olefin reactant.
  • the sum of the equivalents of water and the equivalents of the second hydrogen bond donor is typically between about 0.8 and about 1.2 relative to the amount of olefin reactant. In some embodiments, between about 0.6 and 0.8 equivalents of water and between about 0.2 and 0.6 equivalents of the second hydrogen bond donor are used. In one embodiment, about 0.6 equivalents of water and about 0.2 equivalents of the second hydrogen bond donor are used. In one embodiment, about 0.7 equivalents of water and about 0.2 equivalents of the second hydrogen bond donor are used. In one embodiment, about 0.8 equivalents of water and about 0.2 equivalents of the second hydrogen bond donor are used. In one embodiment, about 0.6 equivalents of water and about 0.6 equivalents of the second hydrogen bond donor are used.
  • the processes of the present invention produce an organic azide product or an azide-containing oligomer or polymer product.
  • the anti-Markovnikov product is the organic azide that results when the azi do group attaches to the less substituted of the olefinic carbons.
  • the olefin reactant is a terminal olefin
  • the anti-Markovnikov product is a primary organic azide.
  • the product is substantially or exclusively the anti-Markovnikov product.
  • the product is a mixture of anti-Markovnikov and Markovnikov products, with the majority in the anti-Markovnikov orientation.
  • the anti-Markovnikov to Markovnikov orientation is in a ratio within the range of about 1:2 to 100:1, or within about 1:11 to 50:1.
  • the ratio of anti-Markovnikov to Markovnikov products is at at least about 1:1.5, at least about 1:1, at least about 2:1, at least about 3:1, at least about 4:1, at least about 5:1, at least about 10:1, at least about 20:1, at least about 50:1, or more.
  • the crude yield of anti-Markovnikov product is at least about 50% (based on the amount of olefin reactant at the beginning of the reaction), at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or greater.
  • the organic azide product is a compound of Formula III:
  • R 1 , R 2 , and R 3 are defined as above.
  • a product of Formula III is formed upon subjecting an olefin reactant of Formula I to the processes described herein, for example the reaction shown in Scheme 1.
  • the product is an azide-containing oligomer or polymer of Formula V:
  • R 10 , R 11 , R 12 , R 13 , and n are defined as above.
  • the product is a mixture of compounds of Formula V having a range of values of n.
  • the product is a mixture of compounds of Formula V wherein n is from 1 to 25, from 5 to 20, from 6, to 19, from 8 to 15, or from 10 to 12.
  • the product is a mixture of compounds of Formula V wherein n is from 10 to 20, from 11 to 20, from 12 to 20, from 13 to 20, from 14 to 20, from 15 to 20, from 14 to 19, from 15 to 19, from 16 to 19, or from 17 to 18.
  • a product of Formula V is formed upon subjecting an olefin of Formula IV to the processes described herein.
  • the process of the present invention may be conveniently carried out in an environmentally friendly non-metal containing one-pot process to create organic azides with anti-Markovnikov selectivity.
  • one-pot is meant that the olefin is combined with all necessary reactants to form the desired product in the same reaction vessel—no transfer and/or isolation of intermediate compounds is necessary.
  • Reaction of the benziodoxole A with the silylazide provides a transient iodine(III) diazide species B which subsequently reacts with the olefin to form a beta-azidoalkyl radical species C. This species is then trapped by hydrazoic acid, formed by reaction of the silylazide and the hydrogen bond donor, to yield the desired organic azide product.
  • Reaction of trimethylsilylazide with water and trifluoroacetic acid provides trimethylsilyl trifluoroacetate and h.ydrazoic acid.
  • Reaction of ttitnethylsilyl trifluoroacetate with the benziodoxole provides the trifluoroacetylated intermediate A, which may either be converted into intermediate B upon reaction with trimethylsilylazide or may form intermediate C upon reaction with another equivalent of trimethylsilyl trifluoracetate.
  • Intermediate B may equilibrate to intermediate C by reaction with trimethylsilyl trifluoroacetate, and intermediate C may equilibrate with intermediate B by reaction with trimethylsilylazide.
  • Intermediate B subsequently reacts with the olefin to form a beta-azido radical species. This radical species is then trapped by hydrazoic acid that was previously formed to yield the desired organic azide product.
  • Reaction of trimethylsilylazide with water and trifluoroacetic acid provides trimethylsilyt trifluoroacetate and hydrazoic acid.
  • the benziodoxole A may subsequently be converted to either intermediate B on reaction with trimethylsilylazide or intermediate C upon reaction reaction with trimethylsilyl trifluoroacetate.
  • Intermediate B may equilibrate to intermediate C by reaction with tritnethylsilyl trifluoroacetate, and intermediate C may equilibrate with intermediate B by reaction with trimethylsilylazide.
  • Intermediate B subsequently reacts with the olefin to form a beta-azido radical species. This radical species is then trapped by hydrazoic acid that was previously formed to yield the desired organic azide product.
  • Any organic solvents may be used in this process that achieves the desired result.
  • exemplary solvents include acetone, ethyl acetate (EtOAc), dichloromethane(Ch 2 Cl 2 ), acetonitrile (MeCN), 1,2-dichloroethane (DCE), nitromethane, hexanes, pentane, toluene, benzene, petroleum ether, 2-butanone, chlorobenzene, chloroform (CHCl 3 ), cyclohexane, heptane, o-xylene, air-xylene, p-xylene, and combinations thereof.
  • the solvent is selected from ethyl acetate (EtOAc), dichloromethane (CH 2 Cl 2 ), or chloroform (CHCl 3 ).
  • the solvent is ethyl acetate (EtOAc).
  • the solvent is dichloromethane (CH 2 Cl 2 ).
  • the solvent is chloroform (CHCl 3 ).
  • the process is typically performed in an organic solvent at a concentration of the olefin reactant if at least about 1.0 molar. In some embodiments, the reaction is performed at an olefin reactant concentration between about 1.0 molar and about 2.3 molar.
  • the reaction is performed at a concentration of the olefin reactant of at least about 1.0 molar, at least about 1.1 molar, at least about 1.2 molar, at least about 1.3 molar, at least about 1.4 molar, at least about 1.5 molar, at least about 1.6 molar, at least about 1.7 molar, at least about 1.8 molar, at least about 1,9 molar, at least about 2.0 molar, at least about 2.1 molar, at least about 2.2 molar, at least about 2.3 molar, or more.
  • the processes of interest are typically performed at room temperature, i.e. a temperature between about 20° C. and 25° C., but may be performed at a lower temperature if deemed necessary, i.e. at a temperature of no less than about 4° C., no less than about 5° C., no less than about 10° C., no less than about 15° C., or no less than about 20° C.
  • the processes of interest may further include appropriate purification and isolation steps to remove impurities and reactants from the product organic azide.
  • the product may be purified the remove the undesired addition product.
  • the processes of interest are suitable for preparation of organic azides on any desired scale, including preparatory/research scale and industrial scale.
  • the reaction vessel in which the processes are carried out may be any convenient size, such as from microliter scale to multi-liter (at least about 5, 10, 100 liters, or greater) scale,
  • Reaction times and reaction conditions will vary and may be determined by reference to the examples and disclosure provided herein, as well as routine experimentation and consultation of the relevant literature when necessary. Typical reaction times are at least about 30 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, or longer. In some embodiments, the processes described herein are run under such conditions so as to achieve the desired result.
  • the process of the present invention can be carried out with isotopic, typically deuterated, compounds or solvents.
  • isotopic typically deuterated, compounds or solvents.
  • Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, the organic promoter, or the hydrogen bond donor may be selected to have at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e. enriched.
  • Isotopes are atoms having the same atomic number but different mass numbers, i.e. the same number of protons but a different number of neutrons.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine such as 2 H, 3 H, 11 C, 13 C, 4 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 I, respectively.
  • the product azide is used to produce an isotopically labeled compound that is employed in metabolic studies (with for example 14 C), reaction kinetic studies (with for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computer tomography (SPECT) including drug or substrate tissue distribution assays.
  • PET positron emission tomography
  • SPECT single-photon emission computer tomography
  • an 18 F labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically labeled compounds produced using this invention can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • isotopes of hydrogen for example, deuterium ( 2 H) and tritium ( 3 H) may be used anywhere in described structures that achieves the desired result.
  • isotopes of carbon e.g., 13 C and 14 C, may be used.
  • Isotopic substitutions for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium.
  • the isotope is 90, 95, or 99% or more enriched in an isotope at any location of interest. In one non-limiting embodiment, deuterium is 90, 95%, or 99% enriched at a desired location.
  • the substitution of one or more hydrogen atoms for a deuterium atom can be provided in any one of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI.
  • the substitution of a hydrogen atom for a deuterium occurs within a group selected from R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6′ ,R 7 , R 7a , R 7b , R 7c , R 8 , R 8′ , R 9 , R 10 , R 11 , R 12 , and R 13 .
  • the alkyl residue may be deuterated (in non-limiting embodiments, CDH 2 , CD 2 H, CD 3 , CH 2 CD 3 , CD 2 CD 3 , CHDCH 2 D, CH 2 CD 3 , CHDCHD 2 , OCDH 2 , OCD 2 H, OCD 3 , etc.).
  • the unsubstituted carbons may be deuterated when two substituents are combined to form a cycle.
  • a process is provided for the synthesis of a beta-deuteroalkyl azide of Formula VI as illustrated in Scheme 3 above, wherein R 1 , R 2 , R 3 , R 4 , and the organic promoter are defined as above; and the deuterium bond donor consists of deuterium oxide and optionally a deuterated acid selected from trifluoroacetic acid-d, acetic acid-d 4 , trifluoromethanesulfonic acid-d, methanesulfonic acid-d 4 , and formic acid-d 2 .
  • the deuterium is 100% incorporated into the product of Formula VI.
  • the deuterium is partially incorporated into the product of Formula VI, for example, about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% , 99%, 99.9%, 99.99%, or 99,999% incorporated.
  • a process is provided for the synthesis of deuterated azide-containing oligomer or polymer of Formula XI as illustrated in Scheme 4 above, wherein R 4 , R 10 , R 11 , R 12 , R 13 , and the organic promoter are defined as above; and the deuterium bond donor consists of deuterium oxide and optionally a deuterated acid selected from trifluoroacetic acid-d, acetic acid-d 4 , trifluoromethanesulfonic acid-d, methanesulfonic acid-d 4 , and formic acid-d 2 .
  • the deuterium is 100% incorporated into the product of Formula XI.
  • the deuterium is partially incorporated into the product of Formula XI, for example, about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.9%, 99.99%, 99.999% incorporated,
  • An organic azide as formed by the present process may be the final desired product, or it may be used as an intermediate through one or more additional reactions to provide a final desired. nitrogen-containing product.
  • the reactions of organic azides have been extensively studied, the results of which are summarized in several reviews (see Brase, S. et al. Angewanche Chemie Internation Edition 2005, 44, 5188; Huang, D. and Yan. G. Adv. Synth. Catal. 2017, 359, 1600-1619; and Scriven, E. F. V. and Turnbull, K. Chem. Rev. 1988, 88, 297-368; each of which is incorporated herein by reference in its entirety).
  • the process further comprises a subsequent step for transformation of the formed organic azide product.
  • Non-limiting representative examples of possible transformations of the organic azide products are provided below.
  • An organic azide may be reacted with an alkyne in the presence of a metal catalyst to provide a triazole (see Tornoe, C. W. et al. Journal of Organic Chemistry 2002, 67, 3057; and Rostovtsev, V. V. et al. Angewandte Chemie International Edition 2002, 41, 2596).
  • a representative example of this reaction is provided in Scheme 8 wherein R A is alkyl optionally substituted with aryl and R B is alkyl optionally substituted alkoxy, aryloxy, or aryl.
  • R A and R B are independently any variable defined herein.
  • An organic azide may be converted to thermally, photochetnically, or with a metal catalyst into a reactive nitrene intermediate that may subsequently undergo a number of transformations such as cycloadditions or C—H insertions (see Dequirez, G. et al. Angewandie Chemie Internation Edition 2012, 51, 7384 for a review of modern nitrene chemistry).
  • a representative example of this type of reaction is provided in Scheme 9:
  • An organic azide can be reacted with a trialkyl or triaryl phosphine to form an iminophosphorane (see Gololobov, Y.G. and Kasukhin, L.F. Tetrahedron 1992, 48, 1353).
  • This iminophosphorane intermediate can be reacted with water to form a primary amine or with an electrophile such as a ketone to form an imine.
  • a representative example of these types of reactions is provided in Scheme 10 wherein R is alkyl or aryl, and R C and R D are independently selected from hydrogen and alkyl optionally substituted with aryl. In an alternative embodiment, R, R C and R D are independently any variable defined herein.
  • processes are also provided for the conjugation of olefin-containing molecules to biomolecules of interest, i.e. for the covalent linkage of olefin-containing compounds to biomolecules of interest.
  • An organic azide or azide-containing oligotner or polymer formed from an olefin using the processes described herein can be conjugated to an alkyne-containing modified biomolecule using an azide-alkyne cycloaddition reaction.
  • a process for the conjugation of an organic molecular ligand group to a modified biomolecule, wherein the organic molecular ligand contains an alkenyl group and the modified biomolecule contains an alkynyl group is provided comptising:
  • a process for the conjugation of an azide-containing oligomer or polymer formed from an organic molecular ligand to a modified biomolecule, wherein the organic molecular ligand contains an alkenyl group and the modified biomolecule contains an alkynyl group comprising:
  • the biomolecule can be a polypeptide including a protein, a polynucleotide such as a polydeoxyribonucleotide or a polyribonucleotide, a monosaccharide or polysaccharide, or a lipid or lipid-like molecule.
  • the organic molecule may be a substrate, an inhibitor, a drug, a fluorescent probe, or any other olefin-containing group that may be useful to conjugate with a biomolecule for any purpose.
  • Step (c) in any embodiments of the bioconjugation process can be performed ex vivo, in vitro, or in vivo depending on the desired application.
  • reaction of the azidoalkyl group of the alkynyl group of the modified biomolecule occurs via a copper-catalyzed azide-alkyne cycloaddition (CuAAC) (see Tornoe, C. W. et al. Journal of Organic Chemistry 2002, 67, 3057; and Rostovtsev, V. V. et al. Angewandte Chemie International Edition 2002, 41, 2596, the entireties of which are incorporated herein by reference).
  • CuAAC copper-catalyzed azide-alkyne cycloaddition
  • the CuAAC reaction can be performed over a wide range of temperatures (0-160° C.) and pH values (4-12), and can even be performed in water.
  • sodium ascorbate is used as a reducing agent for the copper catalyst in a 3- to 10-fold excess, but hydrazine and hydroxylamine have also been used.
  • Copper-stabilizing ligands may be also added to prevent unwanted copper-mediated oxidation of any functionality of the biomolecule, for example histidine and arginine residues in a polypeptide.
  • Representative examples of copper-stabilizing ligands as used in bioconjugation applications include:
  • R L can be benzyl, tert-butyl, or 3-hydroxypropyl.
  • the reaction of the azidoalkyl group of the alkynyl group of the modified biomolecule occurs via a strain-promoted azide-alkyne cycloaddition (SPAAC).
  • SPAAC strain-promoted azide-alkyne cycloaddition
  • the alkenyl group as used in the SPAAC reaction is housed within a cyclooctynyl ring.
  • the high degree of ring stain (18 kcal/mol) allows the reaction to proceed under mild conditions with relatively fast reaction times.
  • Solubility of the cyclooctynyl group in water can typically be increased by the inclusion of polyethyleneglycol (PEG) or sulfonate groups along the point of attachment to the biornolecule.
  • PEG polyethyleneglycol
  • the SPAAC reaction typically results in a mixture of 1,4-triazole regioisomers.
  • R E is the biomolecule or a modified derivative thereof.
  • a photolabile “caged” cyclooctynyl variant is used. These variants reveal the reactive alkyne functionality upon exposure to 350 nm light, allowing for spatially controlled bioconjugation reactions.
  • a representative example of photoinduced cyclooctynyl release is provided in Scheme 11 below wherein R F is a substituted or unsubstituted alkyl. In an alternative embodiment, R F is any van able defined herein.
  • the alkyne group may be installed on the biomolecule in its intact state or may be incorporated into the biomolecule during synthesis or through post translational modification.
  • the functionalization of intact biomolecules to form modified biomolecules as described herein typically occurs by N-hydroxysuccinimide (NHS) mediated amide bond formation with an amine or carboxylic acid functionality on the biomolecule or by substitution of a thiol group on the biomolecule with a maleimide group.
  • NHS N-hydroxysuccinimide
  • NHS esters are commonly used to functionalize amino groups on biomolecules due to their aqueous compatibility and selectivity for primary amines on lysine residues or at the N-terminus of polypeptides.
  • a representative example of addition of an alkynyl group using an NHS ester is provided in Scheme 12 below:
  • R E is the biomolecule or a modified derivative thereof.
  • other functional groups such as alcohols and thiols may alternatively be modified.
  • carboxylic acid functional groups on the biomolecule can be functionalized via in situ formation of the NHS ester by reaction with NHS and a coupling reagent (for example DCC or EDC) followed by subsequent reaction with an amino-substituted alkyne reagent.
  • a coupling reagent for example DCC or EDC
  • R E is the biomolecule or a modified derivative thereof.
  • Functionalization reactions involving NHS esters can be run in aqueous buffers at a pH of 7 to 9 for larger biomolecules, but may be run in organic solvents for smaller biomolecules that do not require aqueous solvation.
  • amine-containing buffers such as tris or glycine should be avoided except to quench the functionalization reaction upon completion. Additional details about using NHS esters to functionalize biomolecules can be found in Chan, A. O. et al. Journal of the American Chemical Society 2012, 134, 2589-2598, incorporated herein by reference in its entirety.
  • Thiol groups present on biomolecules may be functionalized with an alkyne group by reaction with a substituted maleimide reagent.
  • a representative example of this type of functionalization is provided in Scheme 14 below:
  • R E is the biomolecule or a modified derivative thereof.
  • Functionalization reactions involving NHS esters can be run in aqueous buffers at pH 6 to 8. At lower pH values, the reaction tends to be slower but to produce more of the thioether product, while at higher pH values the reaction proceeds faster but with higher levels of hydrolysis of the formed product.
  • thiol-containing buffers such as dithiothreitol (DTT) and beta-mercaptoethanol (BME) should be avoided when using this functionalization procedure. Additional details about using maleimides to functionalize biomolecules can be found in: Fontaine, S. D. et al: Bioconjugate Chemistry 2015, 26, 145-152; and Northrup, B. H. et al. Polymer Chemistry 2015, 6, 3415-3430; each of which is incorporated herein by reference in its entirety.
  • the alkyne functional group may be incorporated into the sequence of a polypeptide by using an unnatural amino acid (UNA) that contains the alkyne functional group.
  • UAA unnatural amino acid
  • the alkyne functional group may be placed via site-specific functionalization, wherein a single amino acid in the polypeptide contains the modification, or by residue-specific functionalization, wherein a particular amino acid is replaced quantitatively throughout the polypeptide. Additional details about using UAAs to functionalize biomolecules can be found in: Kim, S. et al. Bioorganic and Medicinal Chemistry 2016, 24, 5816-5822; Maza., J. C. et al. Bioconjugate Chemistry 2015, 26, 1884-1889; Zimmerman, E. S. et al. Bioconjugate Chemistry 2014, 25, 351-361; and Swiderska, K, W. et al. Bioorganic and Medicinal Chemistry 2017, 25, 3685-369:3; each of which is herein incorporated by reference in its entirety.
  • UAAs that may be used during solid phase peptide synthesis to incorporate an alkyne functional group include:
  • site-specific functionalization can be used for polypeptides that cannot be formed using solid phase peptide synthesis by using an engineered tRNA unique for the target codon in the polypeptide's mRNA sequence.
  • UAAs are included in cell growth medium and incorporated into the primary sequence of the expressed polypeptide. Residue-specific functionalization tends to provide heterogeneous incorporation of the UAAs that may result in altered physical and chemical properties of the polypeptide.
  • Representative examples of UAAs that may be used in these approaches to incorporate an alkyne functional group include:
  • heterobifunctional linker containing the alkyne functionality and either a carboxylic acid or amine moiety may be placed on either the N-terminus or C-terminus of the peptide, respectively, as the final step of solid phase peptide synthesis.
  • heterobifunctional linkers that may be used in this type of approach include:
  • heterobifunctional linkers as described above in bioconjugation include: Sola, L. et al. Langmuir 2016, 32, 10284-10295; Bayramoglu, G. et al, Industrial & Engineering Chemistry Research 2014, 53, 4554-4564; Ciao, Y. et al. Industrial & Engineering Chemistry Research 2014, 53, 16777-16784; Hartwell, B. L. et al. Biomacromolecules 2017, 18, 1893-1907; Nuhn. L. et al. Angewandte Chemie International Edition 2013, 52, 10652-10656; Gori, A. et al. Bioconjugate Chemistry 2016, 27, 2669-2677; Goswami, L. N.
  • post-translational modifications that contain an alkyne functional group can be used.
  • the post translational modification may comprise an alkyne-containing modified sugar, modified lipid, or modified isoprenoid derivative.
  • an acetylated modified sugar may be added to growth medium, and subsequent to internalization, nonspecific hydrolases and esterases remove the acetate groups and release the modified sugar bearing the alkyne group.
  • the modified sugar may subsequently glycosylate proteins of interest, allowing for later conjugation.
  • modified sugars containing alkyne groups that may be used for post-translational modifications include:
  • modified lipids or isoprenoids containing alkyne groups that may be used for post-translational modifications include:
  • alkyne modified nucleic acids or membrane components may be used to install a reactive handle in actively synthesized DNA, RNA, or cell membranes within a cell.
  • modified nucleotides that may be incorporated into polynucleotides for bioconjugation include:
  • a representative example of a modified phospholipid precursor that may be used for cell membrane bioconjugation includes:
  • Stainless steel syringes and cannula were used to transfer air- and moisture-sensitive liquids. Flash chromatography was performed using silica gel 60 (230-400 mesh) from Sigma-Aldrich.
  • 1-Dodecene is commercially available and was distilled before use.
  • the organic phase was separated from the aqueous phase, and the aqueous phase was extracted with hexanes (3 mL ⁇ 3). The combined organic phase was washed with brine (2 mL) and dried over Na 2 SO 4 . After concentration in vacuo, the residue was purified through column chromatography (100% hexanes) to afford 1-azidododecane as colorless oil (192 mg, 91% yield).
  • the organic phase was separated from the aqueous phase, and the aqueous phase was extracted with hexanes (3 mL ⁇ 3). The combined organic phase was washed with brine (2 mL) and dried over Na 2 SO 4 . After concentration in vacuo, the residue was purified through column chromatography (100% hexanes) to afford 1-azidododeca.ne as colorless oil (190 mg, 90% yield).
  • 2-Methylnon-l-ene is commercially available and was distilled before use.
  • (+)-Camphene is commercially available and was used directly without further purification.
  • Allybenzene is commercially available and was distilled before use.
  • N-(3-Phenylpropyl)acetamide IR ⁇ max (neat)/cm ⁇ 1 : 3284 (w), 1647 (s), 1551 (s), 1496 (m), 1454 (m), 1437 (m), 1368 (m), 1266 (s), 1031 (w), 733 (s), 699 (s); 1 H NMR.
  • Allyltriisopropylsilane was prepared using a known procedure (see Murakami, K. et al. The Journal of Organic Chemistry 2009, 74, 1415).
  • But-3-en-1-yl benzoate was prepared using a known procedure (see Bogen, S. et al. Bioorganix & Medicinal Chemistry Letters 2008, 18, 4219).
  • 2,2,2-Trichloroethyl allylcarbamate was prepared using a known procedure (see Kazuhiro, M. et al. Bulletin of the Chemical Society of Japan 1987, 60, 1021).
  • Pent-4-enoic acid is commercially available and was used directly without further purification.
  • But-3-en-1-ol is commercially available and was distilled before use. The reaction was carried out on a 1.0 mmol scale. Procedure 1 of Example 1 was applied with several modifications: no external proton source (H 2 O or trifluoroacetic acid) was added; and the reaction was quenched with aqueous HCl (1 M, 1.5 mL,) and stirred for 15 minutes for protodesilylation of the alcohol functional group. The crude product was purified through column chromatography (hexanes/EtOAc: from 100:1 to 3:1) to afford 4-azidobutan-1-ol as a colorless oil (92 mg, 80% yield) which is a known compound (see Khiar, N. et al. The Journal ref Organic Chemistry 2009, 74, 6002).
  • 3-Methylbut-2-en-l-yl benzoate was prepared using a known procedure (see Yasui, K. et al. The Journal of Organic Chemistry 1995, 60, 1365).
  • Dec-9-enal was prepared using a known procedure (see 1,,ee, R.A. and Donald, D.S. Tetrahedron Letters 1997, 38, 3857). The reaction was carried out on a 1.0 mmol scale. Procedure 2 of Example 2 was applied with some modification. 0.2 equiv of 1-hydroxy-1 ⁇ 3 -benzo[d][1,2]iodaoxol-3(1H)-one, 3.0 equiv of trimethylsilylazide, and 0.6 equiv of trifluoroacetic acid were used. The crude product was purified through column chromatography (hexanes/EtOAc: from 100:1 to 10:1) to afford 10-azidododecanal as a colorless oil (140 mg, 71% yield).
  • 6-Bromohex-1-ene is commercially available and was distilled before use.
  • 1,7-Dichloro-4-methyleneheptane was prepared using a known procedure (see Zhang, C. W. et al. Journal of the American Chemical Socieiy 2013, 135, 14082.
  • Diethyl 2,2-diallylmalonate was prepared using a known procedure (see Krafft, M. E. et al. The Journal of Organic Chemistry 2002, 67, 1233),
  • 5 ⁇ -Cholestan-3 ⁇ -ol is commercially available and was used directly without further purification.
  • the reaction was cooled to 0° C., EtOAc (2 mL) and saturated NaHCO 3 solution (1.5 mL) were added to quench the reaction and to remove any residual hydrazoic acid.
  • the organic phase was separated from the aqueous phase, and the aqueous phase was extracted with EtOAc (3 mL ⁇ 3).
  • the combined organic phase was washed with brine (2 mL) and dried over Na 2 SO 4 .
  • Methyl 2,3,4-Tri-O-methyl- ⁇ -D-glucopyranoside was prepared using a known procedure (see Boultadakis-Arapinis, M. et al, Chemistry—A European Journal 2013, 19, 6052).
  • the reaction was cooled to 0° C., EtOAc (2 mL) and saturated NaHCO 3 solution (1.5 mL) were added to quench the reaction and to remove any residual hydrazoic acid.
  • the organic phase was separated from the aqueous phase, and the aqueous phase was extracted with EtOAc (3 mL ⁇ 3).
  • the combined organic phase was washed with brine (2 mL) and dried over Na 2 SO 4 .
  • 1-Dodecene is commercially available and was distilled before use.
  • Boc 2 O (2.36 g, 10.8 mmol, 1.2 equiv) in THF (10 mL) was added to the above mixture drop-wise at 22° C.
  • the resulting mixture was stirred for additional 2 h until the amine intermediate was fully consumed (monitored by TLC).
  • concentration in vacuo the residue was subsequently purified through column chromatography (hexanes/EtOAc: from 50:1 to 10:1) to afford tert-butyl dodecylcarbamate as a white solid (2.08 g, 81% yield, m.p. 37-39° C.).
  • 1-Dodecene is commercially available and was distilled before use.
  • Styrene is commercially available and was distilled before use.
  • Ethyl acrylate is commercially available and was distilled before use.
  • Ethyl acrylate is commercially available and was distilled before use.
  • Freshly distilled trimethylsilylazide (656 ⁇ L, 5.0 mmol, 2.5 equiv) was added to the reaction and the mixture was stirred for 4 h at 22° C.
  • the reaction was cooled to 0° C., Hexanes (4 mL) and saturated NaHCO 3 solution (2 mL) were added to quench the reaction and to neutralize any residual hydrazoic acid.
  • the organic phase was separated from the aqueous phase, and the aqueous phase was extracted with hexanes (4 mL ⁇ 3).
  • the combined organic phase was washed with brine (4 mL) and dried over Na 2 SO 4 .
  • the reaction mixture was warmed up to 50° C. and stirred for 8 h (monitored by IR until the absorption of azido groups disappeared).
  • the reaction mixture was cooled to room temperature, Et 3 N (1171 ⁇ L, 0.84 mmol, 2.0 equiv), A c2 O (79 ⁇ L, 0.84 mmol, 2.0 equiv) and a solution of DMAP (10 mg, 0.08 mmol. 0.2 equiv) in THF (0.5 mL) were added to the above mixture at 0 ° C.
  • the reaction mixture was warmed up to room temperature and kept stirring for additional 2 h until the intermediate was consumed (monitored by TLC).
  • Freshly distilled trimethylsilylazide (656 ⁇ L, 5.0 mmol, 2.5 equiv) was added to the reaction followed by CF 3 CO 2 D (108 ⁇ L, 1.4 mmol, 0.7 equiv), and the mixture was stirred for 4 h at 22° C.
  • the reaction was cooled to 0° C., hexanes (4 mL) and saturated NaHCO 3 solution (2 mL) were added to quench the reaction and to neutralize any residual hydrazoic acid.
  • the organic phase was separated from the aqueous phase, and the aqueous phase was extracted with hexanes (4 mL ⁇ 3) The combined organic phase was washed with brine (4 mL) and dried over Na 2 SO 4 .

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